Chlorinated derivatives of 1-pyridindene and their preparation



'tion of medicinals.

Patented Mar. 27, 1951 onnoltma'rsn DERIVATIVES F ly-PYRID- IN DENE' AN D THEIR PREPARATION John Thomas Plati, Passaic, and Wilhelm Wenner, Montclair N. 5., assignorsto Hofimaim- La Roche Inc, 'N-fltley, N; J., a cor oration of New Jersey No Drawing. ApplicationMar'ch 4,1950, Serial N0. 147,755

11 Claims.

" This invention relates to new chlorinated deriv'atives' of l-pyridindene,. and to processes of making the same; and more particularly relates to 2 methyl-7-chloro-9-p chlorophenyl-a di hydro-l pyridindene, 2i methyl '7-chl'oro'-9*-pchlorophehyl-ZB, i tetrahydro l pyridin'dene, 'amitheir salts. The parent ring system, 1- pyridindene, and various compounds derived from that system have previously been disclosed in our Patent No. 2,470,109, granted May 117., 1949.

The system of nomenclature employed in thatpatent to identify thev derivatives of l pyrid inclene is followed in'the present disclosure also.

The new derivatives are useful in the prepara- In particular, acid addition saltsof 2' methyl 7-chloro-Q-p-chlorophenyl- 2,3,4,9'-tetrahydro-L-pyridindene have spasmolytic properties.

Briefly, the new compounds may be prepared in the following manner: Pai'a'chloi'o-acetophenone is reacted with methylamin-e hydrochloride and formaldehyde to produce N ,N-bi's-(c-p chlorobenzoylethyl) -methy1amine hydrochloride. The latter is cycli'zed by treatment with sodium h'ydioxide to produce I-methyl-3-p-chlorobemoyl- 4-hydroxy-4-p chloropnenyl piperidi'ne. This piperidine derivative is treated with concentrated aqueous hydrobromic acid (for example; having a concentration of about 40-48 per cent); resulting in further cyclization to produce '2-methyI 7- chloro 9 p chl0rophenyl--2',3-dihydro-1-pyri-' dindene hydrobromide. Alternatively; the same compound may be produced directly from N,N- bis-('/3-p chlorobenzoylethyl) methylami nehy treatment with strong aqueous hydrobrom-io aaid. By hydrogenation of. the 2-methyI-'7-chloro-9 p- 'chlin'biah'eh yl m3*dihydro-1-pyridindene or an acid salt thereof, the corresponding tetrahyd'ro 4 derivative, that is, 2"-meth yl- 'Z -chloro.-9 -p-chlorophenykaSAQ-tenahydm 1 pyridinde'ne or an acid salt ithereof, is obtained; Thetetrahydro deriva'tive can be isolated directly as the hydrobromi'de, but is more conveniently isolated aftereo-nverslonto the corresponding thiocyanate. The free base may be obtained by careful addition of, alkali to the thiocyanat'e. Other acid addition gsalts may be prepared, such as the hydrochloridefthe tartrate, and the maleate; for examgilejbyreacting the free base with the appropriate:;acid. Similarly, quaternary, salts may be prepared'slmh as the methobrom-ide, the methiodide, and the methosulfate; for example, byv

treating the free basewith the appropriate quaternizing agent. :KIIhe following. examples illustrate the {invention, but should not be deemed to limit the invention, since equivalents to the embodiments specifically described will. be obvious to those skilled in the art. I

EXAMPLE 1 N,N-bis'--(e-p'-chZorobnzOy-Zethyl) met-hy' lamine hydrochloride A mixture of 78 g. of p-'chloroacetophlenone, 16 g. of paraformaldehyde, and l7 g. of 'methylain-ine hydrochloride was heated with stirring to a ternperature of about lflfl llflbl I A vigorous re action ensued; heating and stirring were discontinned, and the reaction mixture was cooled.

Whenit had reached a temperature of about 509-69? 0., 200 cc. or acetone were acdedand stirring was resumed. "The crystalline solid which formed was filtered off and recrystallized fr iii ethanol. It was identified as N,l T-bis -Z E-}J= chloroben'zoylethyl) -m'ethylamine hydrochloride, M. 1?. approximately 1'60-'162' C.

1-metizyl 3 a p chlorobenzoyl-el-hydrowy fip- 'chloropheny'l piperidine To 100 cc. of boiling water were added 10 g. of

N,N-bis- (,8-p chlorobehzoylethyl) e m'ethylainine hydrochloride, and then so cc. of it per cent sodium hydroxide. The mixture was stirred and allowed to cool; The crystalline solid which separated was filtered on, recrystallized from benzene, and identified as 1-methy1-3-p-ch1oroben'zoyl-4-hydroxy 4-p-chloro1ohenyl piperidihe, P. approximately 156-159' C. By reaction of the base with hydrochloric acid, the correspond;- ing hydrochloride was obtained, M P; ai -uproar m'ately 192 -19? c-.- i v EXAMPLE '3 z mcthyl-hchloro-e-p h chZomphem l 2 3 a die hydro l pyridindene A mixture of 24.4 of 1-;metny1-3=p-chiorobenzoyii-hyd-roxy-e mnmrcphenyi pi ermineand 126 cc o ir l8 per cent hydroloroinic was refluxed, while stirring, for a period of about 7%: hours The reaction mixture was allowed to stand for 15 hours and the erystaume precipa tate which formed wasyfiltered off, washed with 10 per cent hydrobromic acid, then with water,

and finally recrystallized from per cent suspension of this hydrobromide, the free base, 2- methyl-7-chloro-9-p-chlorophenyl-2,3 dihydrol-pyridindene, was obtained as a viscous oil.

EXAMPLE 4 Z-methyl 4 .i e chloro-9 p-chZrophenyZ-2,3-dihydro-I-pyridindene A mixture of 724 g. of N,N-bis-(c-pchlorobenzoylethyl) -methylamine hydrochloride and 2900 cc. of 48 per cent hydrobromic acid was refluxed, while stirring, for 11 hours. The reaction mixture was cooled and allowed to stand at a temperature of about 20-30 C. for 15 hours. The crystalline solid formed was then filtered off, washed with 20 per cent hydrobromic acid, then with water, and finally crystallized from 7 l. of ethanol. The product was identified as Z-meth- I EXAMPLE 6 2-methyZ-7-chZoro-9-p-chlorophenyl-2,3,4,9-tetrahydro-I-pyridindene hydrobromz'de A mixture of 20 g. of 2-methyl-7-chloro-9-pchlorophenyl-2,3-dihydro-l-pyridindene hydroyl-7-chloro-9-p-chlorophenyl- 2,3-dihydro-l-pyridindene hydrobromide, M. P. approximately 20'8210 C.

. EXAMPLE 2 methyZJ-chloro-9-p-chlorophenyZ-2,3,4,9-tetrahydro-I -pyrz'dindene A mixture of 30 g. of 2-methyl-7-chloro-9-pchlorophenyl- 2,3 -dihydro l pyridindene hydrobromide, 160 cc. of ethanol, and 50 g. of Raney nickel catalyst was hydrogenated at 30 C. under a hydrogen pressure of about 3.5 atmospheres for about 2 /2 hours.

The reaction mixtures resulting from five identical batches, prepared in the manner above described, were combined. The catalyst was filtered off, and the filtrate was distilled at about 50 C. in vacuo (about 20 mm. Hg.) to remove the solvent. The residue was dissolved in 3400 cc. of warm water (approximately 50-60 C.) The solution was cooled to 37 C. and mixed with a solution of 170 g. of potassium thiccyanate in 340 cc. of water. stand for two hours, and the supernatant liquid was decanted from a heavy viscous precipitate which had settled on the bottom of the container. The precipitate was washed by decantation with 550 cc. of water and was then crystallized from 315 cc. of ethanol, yielding a product identified as 2-methyl-7-ch1cro-9-p-chlorophenyl-2,3,4,9-tetrahydro-1-pyridindene thiocyanate, M. P. approximately -2G4-207 C. a

To a suspension of 90 g. of this thiocyanate in 500 cc. of ethanol were added slowly, with shaking, 400 cc. of 10 per cent sodium hydroxide. During the addition of the alkali, the thiocyanate gradually went into solution. After complete addition of the alkali, an oil precipitated. 400 cc. of water were added to the mixture, which was then allowed to stand at about 20-30 C. for hours. At the end of this time, the oil had solidified. The solid cake was broken up, filtered off, and

dissolved in 400 cc. of ethanol at about 50 C.-

Approximately 120 cc. of water were added to the solution, resulting in a slight turbidity; and the mixture was again allowed to stand for a period of 15 hours at about 3-8 C. The crystals which formed were filtered off, washed with 50 per cent alcohol, and dried in a vacuum desiccator over potassium hydroxide at about 3-8 C. The product was identified as the-free base, Z-methylpyridindene, M. P. approximately 90-92f- C.

Toa solution of 5 g. of this tetrahydro base in about 100 cc. of ether was added an ethereal solution of 3 g. of maleic acid. The crystalline product which precipitated was filtered off, washed... with. eth r. dried.. and. identified .as

The mixture was allowed to from alcohol.

bromide, cc. of ethanol and 30 g. of Raney nickel catalyst was hydrogenated at 35 C. under a hydrogen pressure of about 3.5 atmospheres for about 3 hours. The catalyst was filtered off, and the filtrate was distilled at about 50C. in vacuo (approximately 20 mm. Hg.) to remove the sol vent. After standing for about five days, the residue had not crystallized. It was then dis solved in 60 cc. of acetone, and the solution was allowed to stand for 20 hours at approximately 20-25 C. The crystals which formed were filtered ofi, washed with acetone, and recrystallized The product thus obtainediwas identified as 2-methyl-7-chloro 9 p-chlorophen yl-2,3,4,9-tetrahydro-' l -'pyridindene hydrobr0=i mide, M. P. approximately 218-22-2 C.

EXAMPLE 7 2-methyl-7 -chloro-9-p-chlorophenyZ-2,3,4,9-., j

' tetra-1 -pyridindene methiodide methy1-7-ch1oro-9- p-chlcropheny1-2,3,4,9-tetrae hydro-l-pyridindene methiodide, M. P. approx? mately 247-248 C. r We claim: 1

1. A compound selected from the group cons.

, sisting of 2-methyl-'7-chloro-9-p-chlorophenyle 2,3-dihydro-1-pyridindene, 2-methyl-7-chloro-9- p-chloropheny1-2,3,4=,9-tetrahydro-l-pyri-dindene, and their salts.

2. 2-methyl-7-chloro 9 p chlorophenyl-ZB-y dihydro-l-pyridindene.

3. A salt of the compound of claim 2. f 4. Z-methyl-l-chloro-9-p-chlorophenyl-2,3,4,9-: tetrahydro-l-pyridindene. 5. A salt of the compound of claim 4. I .f A hydrohalide of the compound of claim 7. Amaleate of the compound of-claim 4. a 8. A process of producing a compound selected from the group consisting of 2-methyl-7-chloro- 9-p-chl0rophenyl2,3,4,9-tetrahydro- 1 pyridindene and its salts which comprises hydrogenating a compound selected from the group consistingof 2 -methyl-7-chloro --9-p-chlorophenyl-2,3,-di5 hydro-1pyridindene.and its salts. f 9. A process of producing a' salt: or" Z-methyl-le. chloro-9 p chlorophenyl;=2,3,4;9.i11etrahydro 1e pyridindene which comprises catalytically hydrogenating 2-methyl 7 chloro-9,-p-chlorophenyl- 5 9-p-ch1o1'opheny1-2,3-dihydro-l-pyridindene hydrobromide which comprises cycliz'ing N,N-bis- (,B-p-chlorobenzoylethyl)-methy1amine by means of concentrated aqueous hydrobromic acid.

11. A process of producing 2-methy1-7-ch1oro- 9-p-ch1or0pheny1-2,3,-dihydro-1-pyridindene hydrobromide which comprises cyclizing l-methyl- 6 3-p-ch10robenzoyl-4-hydroxy-4-pchlorophenylpiperidine by means of concenafated aqueous hydrobromic acid. I

JOHN THOMAS PLATI. WILI-IELM WENNER.

No references cited. 

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF 2-METHYL-7-CHLORO-9-P-CHLOROPHENYL2,3-DIHYDRO-1-PYRIDINDENE, 2-METHYL-7-CHLORO-9P-CHLOROPHENYL-2,3,4,9-TETRAHYDRO-1-PYRIDINDENE, AND THEIR SALTS. 